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Ars Pharmaceutica (Internet)

On-line version ISSN 2340-9894

Abstract

PEREZ-ANTON, Elena; THOMAS, M. Carmen; EGUI, Adriana  and  LOPEZ, Manuel Carlos. T-cell exhaustion process during chronic infection caused by intracellular trypanosomatids. Ars Pharm [online]. 2019, vol.60, n.2, pp.65-78.  Epub June 28, 2019. ISSN 2340-9894.  http://dx.doi.org/10.30827/ars.v60i2.9432.

Two of the most important neglected tropical diseases, Chagas disease and leishmaniasis, are caused by protozoan intracellular parasites of the Trypanosomatida order. These infections provoke a high social burden and lead to the death of a large number of patients. The host triggers several immune mechanisms, but in the absence of adequate treatment, the infection becomes chronic and in many cases causes the appearance of serious alterations. T lymphocytes are fundamental cells of the adaptive system and are the main immune elements that orchestrate the cell-to-cell response in the context of intracellular infections. Furthermore, it has been described that continuous and persistent stimulation in response to pathogenic antigens causes loss of antigen-specific functional capacities in the T cell subsets. This process is known as exhaustion. This review explores the results to date of the exhaustion process during chronic infections caused by the trypanosomatid parasites Leishmania spp. and Trypanosoma cruzi. A large amount of evidence shows upregulation of the markers of the exhaustion process, namely, the inhibitory receptors, during these chronic infections. This increased expression is observed in both the CD4+ and CD8+ T cell populations. In parallel, with this increased expression of inhibitory receptors, the loss of antigen-specific functional capacity of these T cells is detected, reducing the lymphoproliferative potential and the ability to produce protective molecules against these parasitic infections, such as Th1-like cytokines, among others. Additionally, a positive correlation between the high coexpression of these inhibitory molecules and the severity of the pathology is demonstrated. Furthermore, T cell populations experience a phenotypic fluctuation in the course of these infections toward the predominance of effector memory subsets with a late or terminal differentiation state. This balancing in turn affects the functional capacity of the T cells and enriches the number of cells with senescent and apoptotic characteristics. Thus, it has been demonstrated the existence of an exhaustion process that affects key populations for the parasite control. However, the role of this process in the progression of the severity of these pathologies is still unknown.

The current drugs used to treat these neglected diseases seem to partially reverse this exhaustion process, denoting a reduction in the high inhibitory receptor expression observed prior to chemotherapies. An improvement in the functional capacity of these T cell populations is also observed, which could be related to the reversion of the dysfunctional process. However, the efforts made to date to evaluate blocking therapies do not lead us to a promising conclusion. It will probably be necessary to test the simultaneous blockade of several pathways and to continue advancing the knowledge to verify their possible use as immunotherapy. It is therefore necessary to continue investigating how this process is triggered and to what extent it influences the appearance of the symptomatology of patients.

Keywords : Chagas disease; leishmaniasis; T-cell exhaustion process; inhibitory receptors; cytokines.

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